Gastric Schwannoma: A Tumor Must Be Included in Differential Diagnoses of Gastric Submucosal Tumors.
Gastric schwannoma (GS) is a rare neoplasm of the stomach. It accounts for 0.2% of all gastric tumors and is mostly benign, slow-growing, and asymptomatic. Due to its rarity, GS is not widely recognized by clinicians, and the precise differential diagnosis between GS and other gastric submucosal tumors remains difficult preoperatively. The present study reports a case of GS misdiagnosed as gastrointestinal stromal tumor and reviews the clinical, imaging, and pathological features, treatment, and follow-up of 221 patients with GS previously reported in the English literature. Although GS is rare, the case reported in the current study highlights the importance of including GS in differential diagnoses of gastric submucosal tumors. Furthermore, the findings of the review suggest that although many cases are asymptomatic, the most common symptoms are abdominal pain or discomfort, not gastrointestinal bleeding, and malignant GSs present with clinical symptoms more commonly. Although large-sample multicenter studies on the efficacy, safety, and oncological outcomes of minimally invasive techniques are required, the findings presented herein may be helpful for clinicians when diagnosing or treating GS.


The Modulatory Role of MicroRNA-873 in the Progression of KRAS-Driven Cancers.
KRAS is one of the most frequently mutated proto-oncogenes in pancreatic ductal adenocarcinoma (PDAC) and aberrantly activated in triple-negative breast cancer (TNBC). A profound role of microRNAs (miRNAs) in the pathogenesis of human cancer is being uncovered, including in cancer therapy. Using in silico prediction algorithms, we identified miR-873 as a potential regulator of KRAS, and we investigated its role in PDAC and TNBC. We found that reduced miR-873 expression is associated with shorter patient survival in both cancers. miR-873 expression is significantly repressed in PDAC and TNBC cell lines and inversely correlated with KRAS levels. We demonstrate that miR-873 directly bound to the 3' UTR of KRAS mRNA and suppressed its expression. Notably, restoring miR-873 expression induced apoptosis; recapitulated the effects of KRAS inhibition on cell proliferation, colony formation, and invasion; and suppressed the activity of ERK and PI3K/AKT, while overexpression of KRAS rescued the effects mediated by miR-873. Moreover, in vivo delivery of miR-873 nanoparticles inhibited KRAS expression and tumor growth in PDAC and TNBC tumor models. In conclusion, we provide the first evidence that miR-873 acts as a tumor suppressor by targeting KRAS and that miR-873-based gene therapy may be a therapeutic strategy in PDAC and TNBC.


A rare case of mitochondriopathy with autosomal dominant progressive external ophthalmoplegia diagnosed through skeletal muscle biopsy.
Mitochondriopathies are a heterogeneous group of genetic diseases of all ages, with a very diverse clinical presentation related to genetic heteroplasmy. The clinical symptoms display a large variability and generally, the more severe phenotypes have an early onset, even from the neonatal period, while milder ones are manifested later in the adulthood. Most publications have already demonstrated deletions or point mutations in mitochondrial deoxyribonucleic acid (DNA), but in recent years, the field of investigation has expanded to syndromes caused by mutations in the nuclear DNA (nDNA), with a Mendelian inheritance. We present the case of a male patient with a mitochondriopathy with phenotype of chronic progressive external ophthalmoplegia (PEO), due to an autosomal dominant mutation in nDNA, in the DNA polymerase subunit gamma (POLG) gene, the pathogenic variant c.2864A>G (p.Tyr955Cys), morphologically investigated and diagnosed using a skeletal muscle biopsy. The aim of this presentation is to emphasize the diagnostic value of the muscle biopsy both in cases of clinical suspicion and in more challenging cases of mitochondrial diseases with atypical or unusual features. Although genetic testing may be the initial test of choice in cases with suggestive clinical presentation, muscle biopsy is an alternative diagnostic aid with high value even in our molecular era. We present pathological and ultrastructural data to confirm the diagnosis.


Increased HCN Channel Activity in the Gasserian Ganglion Contributes to Trigeminal Neuropathic Pain.
Orofacial neuropathic pain caused by trigeminal nerve injury is a debilitating condition with limited therapeutic options. Hyperpolarization-activated cyclic nucleotide-gated (HCN) channels regulate neuronal excitability and are involved in the development and maintenance of chronic pain. However, the effect of HCN channel activity in the Gasserian ganglion on trigeminal neuropathic pain has not been examined. We evaluated nociceptive behaviors after microinjection of the HCN channel blockers ZD7288 or ivabradine into the Gasserian ganglion in rats with trigeminal nerve injury. Both blockers dose-dependently ameliorated evoked and spontaneous nociceptive behavior in rats with trigeminal neuropathic pain. Moreover, the clinically available HCN channel blocker ivabradine showed a prolonged antinociceptive effect. In the Gasserian ganglion, HCN1 and HCN2 are major HCN isoforms. After trigeminal nerve injury, the counts of HCN1 as well as HCN2 immuno-positive punctae were increased in the ipsilateral Gasserian ganglions. These results indicate that the increased HCN channel activity in the Gasserian ganglion directly contributes to neuropathic pain resulting from trigeminal nerve injury. Trigeminal nerve damage-induced orofacial pain is severe and more resistant to standard pharmacological treatment than other types of neuropathic pain. Our study suggests that targeting HCN channel activities in the Gasserian ganglion may provide an alternative treatment of trigeminal neuropathy including trigeminal neuralgia.


TDS exposure project: How and when to consider seasonalityin a total diet study?
Seasonality is a key issue of total diet studies (TDS), as season may impact consumption patterns and concentrations of food chemicals, then exposure levels. This work aimed at analyzing the impact on dietary exposure of different options of seasonality management, to propose guidelines for TDS sampling. Dietary exposure to nine chemicals was assessed for adults and children from the second French Individual and National Food Consumption Survey: arsenic, copper, manganese, dioxins, furans, dioxin-like and non dioxin-like PCBs, deoxinivalenol and ochratoxin A. Seasonality was considered either in both consumption and concentration data, consumption data only, or concentration data only. Results showed significant differences between exposures during different seasons. For most chemicals, the difference between seasonal exposures may not be mainly driven by seasonality of consumption, but partly by seasonality of concentration. Results on risk assessment remained generally the same. If the main objective of the TDS is the risk assessment, considering season for sampling could be costly but with a low added value in terms of results. For exposure refinement, season has to be considered in the sampling design. More particularly, seasonal samples should be kept separately for chemicals with expected seasonal variation in concentrations, such as some metals or mycotoxins.


Epidemiology and psychosocial assessment of COVID-19 among workers of the Nigeria Centre for Disease Control infected with COVID-19.
COVID-19 is a global health crisis. By 2021, Nigeria had 230,000 cases. As the national public health institute, NCDC leads the COVID-19 response. Due to constant contact with infected patients, agency employees are a t high-risk. Here, we describe the transmission and psychosocial effects of COVID- 19 among infected NCDC workers as a learning curve for minimizing occupational transmission among frontline public health workers in future outbreaks. We approved and enrolled all NCDC COVID-19- infected personnel from November to December 2020. We collected data using SurveyMonkey. STATA 14 analyzed the data. 172 of 300 afflicted NCDC staff participated in this study. One-third were between 30 and 39; most were male (104, 60.5%). Most participants worked in the lab (30%) or surveillance (24%). Only 19% (33/172) of participants confirmed pandemic deployment. Most reported interaction with a confirmed case (112/65.1%). Most people (78, 45.3%) felt unhappy when diagnosed. Anger, worry, and low motivation also ranked high (19). The majority reported adequate financial, moral, or psychosocial assistance (26, 70.6%). NCDC staff had a high SARS-CoV-2 infection rate and emotional damage. We urge stricter infection control methods when sending staff for outbreaks response to prevent additional transmission, as well as ongoing psychosocial and economic assistance for afflicted workers.


[Analgosedation of the ventilated intensive care patient].
Seven different schemes for analgesic anaesthesia were investigated for their clinical applicability, potential side effects, and impacts on circulation parameters of the systemic and pulmonary (peripheral) circulation as well as on the intracranial pressure. In all, so patients per group were treated. The results revealed different reactions of patients, such as a higher incidence of disturbances of the autonomic nervous system and excitation after medication withdrawal. Favourable effects not only on clinical reactions but also on circulation parameters were seen during fentanyl/midazolam or alfentanil/midazolam therapy. In several instances, a clear increase in the right atrial and the pulmonary arterial mean pressure as well as the intracranial pressure was observed during ketamine/flunitrazepam therapy. The combinations pethidine/promethazine or pethidine/flunitrazepam also showed clear side effects on the circulation and evoked an increase in the intracranial pressure. Fentanyl/midazolam or alfentanil/midazolam treatments were the most favourable combinations for most of the patients who were artificially respirated.


[Personalized medicine: equity and access].
Personalized medicine has seen a recent increase in popularity amongst medical researchers and policymakers. Nevertheless, there are persistent legal, ethical, and social questions that need to be explored, particularly related to the criticism that personalized medicine constitutes an elitist model of healthcare. Investigating this critique the current manuscript argues that personalized medicine has the potential to become a positive force for equitable access to better healthcare at a national and international level.


Is vitamin D deficiency correlated with childhood wheezing and asthma?
There is increasing evidence that vitamin D regulates immune responses. There is also epidemiological evidence of a relationship between vitamin D deficiency and development of asthma. In addition, several epidemiological studies suggest that low levels of vitamin D during pregnancy and early life are inversely associated with the risk of developing respiratory infections and wheezing in childhood. Vitamin D also seems to reduce asthma exacerbation and increase the response to glucocorticoids. These findings have led to considering a possible link between the occurrence of allergic respiratory diseases and low levels of vitamin D. However, the precise role of vitamin D in the pathogenesis of asthma still remains unclear, emphasizing the need for well-designed trials on vitamin D supplementation to decipher its role in preventing and/or managing the disease. This review examines the relationship that exists between vitamin D deficiency and childhood wheezing and asthma.


Fetal intracranial hemorrhage (fetal stroke): report of four antenatally diagnosed cases and review of the literature.
Neonatal intracranial hemorrhage (ICH) has been estimated to be high in premature infants, occurring in approximately 40% of infants of less than 32 weeks' gestation. However, the true incidence of ICH in utero has not been determined. We present our experience with four cases of fetal ICH (fetal stroke), which was detected prenatally by ultrasonography (US). Four cases of fetal ICH were identified over a 2-year period at the prenatal unit of Taichung Veterans General Hospital, Taiwan. Prenatal and neonatal sonograms, computed tomography (CT) scan or magnetic resonance imaging (MRI), medical records, and the clinical course were assessed retrospectively. In each case, a series of initial and follow-up obstetric sonograms were available. Fetal stroke was recognized by several sonographic features: irregular echogenic brain mass, intraventricular echogenic foci or periventricular echodensities; ventriculomegaly; and posthemorrhagic hydrocephalus (PHH). A detailed investigation for possible etiology of fetal ICH was performed in all cases. Transabdominal US showed hyperechoic lesions in the lateral ventricle and ventriculomegaly in three of the four fetuses, and a massive intraparenchymal hemorrhage in the remaining one. Three fetuses were born vaginally and one by cesarean section due to an enlarged head circumference. Abnormal nonstress tests and abnormal flow velocity waveforms in the umbilical and middle cerebral arteries were present in two cases. Intrapartum fetal death and neonatal death occurred in the first two cases associated with maternal preeclampsia at 31 and 27 weeks, respectively. In the remaining two infants, the one in case 3 underwent ventriculoperitoneal shunting, which developed normally at the age of 18 months. The other infant in case 4 had PHH after suspicious choroids plexus hemorrhage, and the detailed information regarding the cause of neonatal death was not available. This small series demonstrate that an antenatal diagnosis of fetal stroke with intraventricular hemorrhage Grades III and IV or with brain parenchymal involvement appears to be associated with poor neurologic outcome. Due to the significant neonatal neurologic impairment and potential medicolegal implications of antepartum fetal ICH, it follows that obstetricians and sonographers should be familiar with predisposing factors and typical diagnostic imaging findings of rare in utero ICH events.


MicroRNA control of podosome formation in vascular smooth muscle cells in vivo and in vitro.
Smooth muscle cell (SMC) plasticity plays an important role during development and in vascular pathologies such as atherosclerosis and restenosis. It was recently shown that down-regulation of microRNA (miR)-143 and -145, which are coexpressed from a single promoter, regulates the switch from contractile to synthetic phenotype, allowing SMCs to migrate and proliferate. We show in this study that loss of miR-143/145 in vitro and in vivo results in the formation of podosomes, which are actin-rich membrane protrusions involved in the migration of several cell types, including SMCs. We further show that platelet-derived growth factor (PDGF) mediates podosome formation in SMCs through the regulation of miR-143/145 expression via a pathway involving Src and p53. Moreover, we identify key podosome regulators as targets of miR-143 (PDGF receptor alpha and protein kinase C epsilon) and miR-145 (fascin). Thus, dysregulation of the miR-143 and -145 genes is causally involved in the aberrant SMC plasticity encountered during vascular disease, in part through the up-regulation of an autoregulatory loop that promotes podosome formation.


P041 Successful Reduction in Opioid Prescription for IBD Flare in the Emergency Department: A Retrospective Study and Quality Improvement Initiative.
Opioid use is associated with increased mortality, emergency department (ED) utilization, 30-day readmission rates and decreased quality-of-life in patients with inflammatory bowel disease (IBD). Opioid use in the ED for acute IBD presentations has not been well characterized in the literature. Safe, evidence-based, and effective pain management guidance for IBD flares is needed to promote opioid stewardship in the ED. We performed a retrospective cohort study of adult patients who presented to an academic tertiary center ED with IBD flares from June 2019 through December 2019. Demographic and disease specific information and ED course, including analgesic use and numeric rating pain scores at ED presentation and discharge, were collected from the medical record. We designed and implemented a multimodal quality improvement intervention consisting of an evidenced-based IBD pain guideline, customized electronic health record order-set, Gastroenterology (GI) consult note smart-phrase and clinician education to promote opioid stewardship. The impact of our intervention was measured with a repeat retrospective analysis from December 2020 through April 2021. Run charts were generated to correlate the timing of interventions to changes in opioid exposure and prescription. Seventy-one patients were included in the pre-intervention cohort. A total of 78% of patients who presented to the ED with IBD flare were prescribed opioid(s) with an average of 29.3 morphine milligram equivalence (MME) per ED stay. Approximately half (49%) of patients did not receive any non-opioid analgesic and 13% patients received an opioid prescription at ED or hospital discharge. In the post-intervention cohort consisting of 49 patients, there was a significant reduction in the proportion of patients receiving opioids (45% vs. 78%; p < 0.001) and a significant reduction in the average total opioid administration (10.8 vs. 22.6 MME; p < 0.001). For each month during the post-intervention period, the proportion of patients who received an opioid in the ED and the average total opioid administered remained less than the median of the entire study period, which represents a nonrandom pattern. The use of a non-opioid analgesic, IV acetaminophen, was significantly increased (27% vs 3%; p < 0.001) and the risk of new or recurrent gastrointestinal bleeding was negligible in both cohorts (0% vs. 1%; p = 1.0). There was no significant difference between the average pain score (4.9 vs. 5.4 [10-point-scale]; p=0.440) and the difference between reported triage and final ED pain scores (-1.8 vs. -2.0; p=0.729). Furthermore, there was a significant reduction in GI consultation (35% vs. 58%; p <0.016) and a non-significant reduction in hospital admission (63% vs. 80%; p=0.058). Almost 80% of patients who present to ED with IBD flare are prescribed opioids, while only half of patients receive non-opioid analgesics. Also concerning was the high rate of opioid prescription at ED or hospital discharge. A multimodal intervention successfully reduced the proportion and amount of opioid prescribing in the ED without compromising pain control or increasing the risk of GI bleeding. This was also associated with a significant increase in a non-opioid analgesic administration and a significant decrease in GI service consultation. These findings support the role of implementing an evidence-based IBD pain management guideline with electronic prescribing support and education in the ED setting for acute IBD flares. Additional research is needed to determine long-term benefits of reduced opioid exposure in this population.


Participation in a clinical trial influences the future management of patients with gastro-oesophageal reflux disease in general practice.
The long-term effects of participation in trials has not been reported. A randomized-controlled trial (the ONE study) reported on the management of gastro-oesophageal reflux disease with esomeprazole in primary care, testing on-demand treatment vs. treatment courses. To evaluate the impact of participation in a trial on General Practitioners management and patient behaviour. Management of gastro-oesophageal reflux disease was compared between General Practitioners who participated in ONE (ONE-GPs) and a random sample of General Practitioners who did not participate in ONE (Other-GPs). Symptom presentation and satisfaction with treatment was compared between patients who had participated in ONE (ONE-patients) and patients who had not (Other-patients). ONE-GPs prescribed on-demand treatment with proton-pump inhibitors to 47% of the patients, Other-GPs to 27%. ONE-patients consulted for significantly less symptoms compared with Other-patients. ONE-patients reported significantly higher patient satisfaction compared with Other-patients. ONE-patients used 98 doses during 6 months whereas Other-patients used 76 doses. Participation in a clinical trial influenced both doctors and patients. Treatment modalities introduced by the trial were used in daily practice by the General Practitioners. Patients who had participated in the trial consulted for less symptoms and used more medication, compared with patients who did not participate.


A double-mimetic peptide efficiently neutralizes HIV-1 by bridging the CD4- and coreceptor-binding sites of gp120.
The HIV-1 envelope glycoprotein binds cooperatively to its cellular receptor CD4 and a coreceptor, principally CXCR4 or CCR5. We have previously improved a natural amino-acid form of a scorpion toxin-derived CD4-mimetic peptide and in parallel generated sulfopeptide mimetics of the CCR5 amino terminus. Here we show that some fusions of these CCR5- and CD4-mimetic peptides, expressed as immunoadhesins, neutralize HIV-1 more efficiently than CD4-Fc or equimolar mixtures of immunoadhesin forms of each peptide. Specifically, double-mimetic peptides with linkers of 11 amino acids or greater, and with the CCR5-mimetic component preceding the CD4-mimetic component, were more efficient than constructs with shorter linkers or in a reverse orientation. The potency of these constructs derives from (i) their ability to simultaneously and cooperatively bind the CD4- and CCR5-binding sites of a single gp120 monomer of the HIV-1 envelope glycoprotein trimer and (ii) the ability of the CCR5-mimetic component to prevent the CD4-mimetic peptide from promoting infection when cellular CD4 is limiting. Thus, there is a significant advantage to simultaneously targeting both conserved regions of the HIV-1 envelope glycoprotein. This report describes a novel class of peptides that potently inhibit HIV-1 entry. These peptides simultaneously target the receptor- and coreceptor-binding sites of the HIV-1 envelope glycoprotein gp120. Peptides of this class overcome key limitations of inhibitors that target only one gp120 binding region and illustrate the utility of binding the sulfotyrosine-binding pockets of gp120.


Relationship between atrial natriuretic polypeptide and cyclic 3'5'-guanosine monophosphate in human plasma.
To examine the interrelationship between human atrial natriuretic polypeptide (hANP) and cyclic 3'5'-guanosine monophosphate (cyclic GMP), plasma concentrations of these compounds were determined in 61 disease-free humans, as controls, and in 35 patients with congestive heart failure. Levels of plasma hANP (199.6 +/- 53.7 pg/ml) and cyclic GMP (12.6 +/- 1.7 pmol/ml) in patients with congestive heart failure were significantly higher than in the control subjects (hANP 57.1 +/- 2.8 pg/ml, cyclic GMP 5.2 +/- 0.3 pmol/ml). Although plasma hANP concentrations in the patients with congestive heart failure tended to increase with the severity of cardiac dysfunction, there was no significant correlation between the levels of plasma hANP and the grade of heart failure, classified according to the New York Heart Association. However, a significant correlation was found between plasma hANP and cyclic GMP concentrations in both the healthy subjects and the patients with congestive heart failure, and a weak positive correlation between plasma hANP and cyclic 3'5'-adenosine monophosphate (cyclic AMP) concentration in the patients with congestive heart failure. Thus, changes in plasma cyclic GMP concentration depend to some extent on the plasma concentrations of hANP.


Decreased cardiac mortality with nicorandil in patients with ischemic heart failure.
Effective treatments in heart failure (HF) patients with ischemic etiology have not been fully established. Nicorandil, combination of nitrate component and sarcolemmal adenosine triphosphate-sensitive potassium channel opener, is a potent vasodilator of coronary and peripheral vessels and has been used as an antianginal agent. Therefore, we examined impacts of nicorandil on cardiac mortality in ischemic HF patients. Consecutive 334 HF patients with ischemic etiology were retrospectively registered and divided into 2 groups based on oral administration of nicorandil: nicorandil group (n = 116) and non-nicorandil group (n = 218). We retrospectively examined cardiac mortality. In the Kaplan-Meier analysis (mean follow-up period 963 days), cardiac mortality was significantly lower in the nicorandil group than in the non-nicorandil group (11.2% vs. 19.7%, P = 0.032). In the Cox proportional hazard analysis, usage of nicorandil was a suppressor of cardiac mortality (hazard ratio 0.512, 95% confidence interval 0.275-0.953, P = 0.035), and this result was consistent in several subgroup analyses, such as left ventricular ejection fraction, percutaneous coronary intervention, coronary artery bypass graft, diabetes, β-blockers, and statins. Nicorandil is potentially effective for reducing mortality in patients with ischemic heart failure. This was a retrospective study.


Human cytomegalovirus. I. Purification and characterization of viral DNA.
Two human strains (AD-169 and C87) and one simian strain (GR2757) of cytomegalovirus (CMV) have been purified from the extracellular fluids of virus-infected cultures by sedimentation through a sucrose gradient followed by brief centrifugation in a preformed gradient of CsCl. Enveloped virus particles were located in the density region, 1.219 g/cm(3), and nucleocapsids at 1.263 g/cm(3). Purified viral DNA, both human and simian, sedimented in the region of 55S in neutral sucrose gradients with herpes simplex type I DNA as a marker; the molecular weight of the CMV DNA was estimated as approximately 10(8). The density of the viral DNA determined by analytical ultracentrifugation was 1.716 g/cm(3) for the human strains and 1.710 g/cm(3) for the simian strain. Tritiated viral complementary RNA synthesized in vitro with Escherichia coli transcriptase has been used for detection and localization of viral genome in membrane hybridization and in situ cytohybridization. Newly synthesized viral DNA appeared 24 h after infection and localized at two acrocentric areas; later the viral DNA distributed in a band resembling intranuclear inclusions 48 to 70 h after infection. Total DNA synthesis began to increase 24 h after infection and reached its peak at 70 h; RNA synthesis increased at 13 h, and reached its peak at 24 to 33 h. The viral DNA was also labeled with (3)H-TTP by repair-synthesis in vitro with Kornberg's enzyme in order to analyze the purity of the DNA and for detection of viral DNA by DNA-DNA reassociation kinetics.


Skeletal Muscle Quality: A Biomarker for Assessing Physical Performance Capabilities in Young Populations.
Muscle quality (MQ), defined as the amount of strength and/or power per unit of muscle mass, is a novel index of functional capacity that is increasingly relied upon as a critical biomarker of muscle health in low functioning aging and pathophysiological adult populations. Understanding the phenotypical attributes of MQ and how to use it as an assessment tool to explore the efficacy of resistance exercise training interventions that prioritize functional enhancement over increases in muscle size may have implications for populations beyond compromised adults, including healthy young adults who routinely perform physically demanding tasks for competitive or occupational purposes. However, MQ has received far less attention in healthy young populations than it has in compromised adults. Researchers and practitioners continue to rely upon static measures of lean mass or isolated measures of strength and power, rather than using MQ, to assess integrated functional responses to resistance exercise training and physical stress. Therefore, this review will critically examine MQ and the evidence base to establish this metric as a practical and important biomarker for functional capacity and performance in healthy, young populations. Interventions that enhance MQ, such as high-intensity stretch shortening contraction resistance exercise training, will be highlighted. Finally, we will explore the potential to leverage MQ as a practical assessment tool to evaluate function and enhance performance in young populations in non-traditional research settings.


Cardiotoxicity of amitriptyline and doxepin.
The cardiotoxicity of the tricyclic antidepressants amitriptyline and doxepin were compared in an animal with acute overdose. The mean repetitive extrasystole threshold (RET) decreased 71.5% with amitriptyline and 27.5% with doxepin (mean blood levels 933 ng/ml and 1889 ng/ml). Physostigmine reversed these effects. Sodium bicarbonate had a variable effect on the lowered RET. The toxic arrhythmogenic effects of the tricyclic antidepressants can be measured by RET and are partly autonomic tone manipulation. In the same blood level range, doxepin is less toxic than amitriptyline.


Computational study on the interaction between CCR5 and HIV-1 entry inhibitor maraviroc: insight from accelerated molecular dynamics simulation and free energy calculation.
C-C chemokine receptor type 5 (CCR5) is the co-receptor of human immunodeficiency virus type 1 (HIV-1) and plays an important role in HIV-1 virus infection. Maraviroc has been proved to be effective for anti-HIV-1 by targeting CCR5. Understanding the detailed interaction mechanism between CCR5 and Maraviroc will be of great help to the rational design of a more potential inverse agonist to block HIV-1 infection. Here, we performed molecular dynamics (MD) simulation and accelerated MD simulation (aMD) to study the interaction mechanism between CCR5 and Maraviroc based on a recently reported crystal structure. The results of MD simulation demonstrate that Maraviroc can form stable hydrogen bonds with residues Tyr37(1.39), Tyr251(6.51) and Glu283(7.39). The results of aMD simulation indicate that the carboxamide moiety is more flexible than the tropane group of Maraviroc in the pocket of CCR5. The electrostatic potential analysis proves that Maraviroc can escape from the pocket of CCR5 along the negative electrostatic potential pathway during the dissociation process. The free energy calculation illustrates that there exist three binding pockets during the dissociation process of Maraviroc. Our results will be useful for understanding the interaction mechanism between CCR5 and Maraviroc as well as for the rational design of a more potent inverse agonist.


Morphofunctional evidence of changes in principal and mitochondria-rich cells in the epidermis of the frog Rana kl. esculenta living in a polluted habitat.
The epidermis of vertebrates is the body's principal barrier against environment and its possible contaminants. The presence of keratins, as well as specific detoxifying molecules or enzyme activities, in the various epidermis layers is believed to be involved in providing protection from harmful environmental influences. Anuran integument is poorly hornified and thus permeable to some endogenous and exogenous compounds and thus serves as a good bioindicator of overall environmental conditions. In the present investigation, we studied the epidermis of Rana kl. esculenta adult specimens collected at two different rice fields, relatively unpolluted and heavily polluted, respectively. Environmental pollution was assayed by chemical analysis performed on both sediments and animals. We evaluated the structural aspects of the epidermis at both light and electron microscopy levels and the pattern of keratinization by immunohistochemistry. Furthermore, we studied the activities of some enzymes (acid and alkaline phosphatase, nitric oxide synthase-related nicotinamide adenine dinucleotide phosphate dehydrogenase, glucose-6-phosphate dehydrogenase, catalase, nonspecific esterases, and succinic dehydrogenase) involved mainly in membrane transport, xenobiotics, and oxidative metabolism. Compared with controls, in polluted animals we found the following results: (1) an increase in pollutant levels (i.e., cadmium, mercury, and lead); (2) less keratinized superficial cells in the epidermis; and (3) changes in most enzyme activities in keratinocytes and mitochondria-rich cells (particularly glucose-6-phosphate dehydrogenase and esterases, both important to counteract oxidative and toxic stress). Taken as a whole, the present data indicate the morphofunctional plasticity of the frog epidermis in response to environmental contamination.


A 5-year clinical experience with bipolar radiofrequency ablation for permanent atrial fibrillation concomitant to coronary artery bypass grafting and aortic valve surgery.
This study analyses the 5-year results of permanent atrial fibrillation (pAF) bipolar radiofrequency (RF) ablation surgery concomitant to coronary artery bypass grafting (CABG) and/or aortic valve (AV) surgery. Eighty-five patients with pAF (0.5-30 years) underwent bipolar RF ablation procedure concomitant to CABG/AV surgery. All patients were restudied to assess survival, conversion rate to stable sinus rhythm (SR) and New York Heart Association (NYHA) class at 8+/-1 days and at 3+/-1 and 32+/-15 months after surgery. Survival at time of re-examination was 100%, 98% and 96%, respectively (three non-cardiac deaths), SR could be documented in 61%, 74% and 78% of patients. Long-term AF before surgery and larger size of the left atrium (LA) were predictive for postoperative AF return (P=0.005, P=0.03); 88% of patients with small preoperative LA-size (<50 mm) and 85% with pAF-duration time <5 years had stable SR at late follow-up. Cardiac rhythm at three months was predictive for long-term rhythm-prognosis (P<0.0001). NYHA-class improved significantly after surgery (P<0.0005), particularly when SR was achieved (P=0.046). Permanent AF bipolar RF ablation surgery revealed excellent results in AV/CABG patients. It could be demonstrated that established SR remained stable over time. Preoperative pAF-duration time and LA-size are useful variables to predict the success rate of ablation.


Development and psychometric testing of the clinical networks engagement tool.
Clinical networks are being used widely to facilitate large system transformation in healthcare, by engagement of stakeholders throughout the health system. However, there are no available instruments that measure engagement in these networks. The study purpose was to develop and assess the measurement properties of a multiprofessional tool to measure engagement in clinical network initiatives. Based on components of the International Association of Public Participation Spectrum and expert panel review, we developed 40 items for testing. The draft instrument was distributed to 1,668 network stakeholders across different governance levels (leaders, members, support, frontline stakeholders) in 9 strategic clinical networks in Alberta (January to July 2014). With data from 424 completed surveys (25.4% response rate), descriptive statistics, exploratory and confirmatory factor analysis, Pearson correlations, linear regression, multivariate analysis, and Cronbach alpha were conducted to assess reliability and validity of the scores. Sixteen items were retained in the instrument. Exploratory factor analysis indicated a four-factor solution and accounted for 85.7% of the total variance in engagement with clinical network initiatives: global engagement, inform (provided with information), involve (worked together to address concerns), and empower (given final decision-making authority). All subscales demonstrated acceptable reliability (Cronbach alpha 0.87 to 0.99). Both the confirmatory factor analysis and regression analysis confirmed that inform, involve, and empower were all significant predictors of global engagement, with involve as the strongest predictor. Leaders had higher mean scores than frontline stakeholders, while members and support staff did not differ in mean scores. This study provided foundational evidence for the use of this tool for assessing engagement in clinical networks. Further work is necessary to evaluate engagement in broader network functions and activities; to assess barriers and facilitators of engagement; and, to elucidate how the maturity of networks and other factors influence engagement.


Blue Multifocal Pupillographic Objective Perimetry in Glaucoma.
This study investigated multifocal pupillographic objective perimetry (mfPOP) stimuli that target the intrinsic photosensitivity of melanopsin retinal ganglion cells. The diagnostic potential for glaucoma is compared between stimuli biased toward either cone input to these cells or their melanopsin response. Nineteen glaucoma patients and 24 normal subjects were tested using mfPOP stimulus protocols with either 33-ms yellow or 750-ms blue stimuli. Subjects' color discrimination was assessed using the Farnsworth 100-hue test. Pupillary responses were measured, and mixed-effects regression was used to quantify results. Diagnostic accuracy was assessed using receiver operating characteristic (ROC) analysis. The mean reduction in moderate to severe glaucoma pupil responses using blue mfPOP stimuli was larger but more variable than that of the shorter yellow stimuli (blue: -1.32 dB [t(40) = -2.29; P = 0.027]; yellow: -0.93 dB [t(40) = -3.13; P = 0.003]). Color discrimination decreased significantly with age and glaucoma, with type III blue-yellow anomalies dominating. ROC analysis revealed similar diagnostic accuracies (AUC for eyes classified as moderate to severe; blue: 81.7%, yellow: 83.7). Slightly higher sensitivity and specificity were obtained using blue stimuli in mild disease (AUCs blue: 71.1, cf. yellow: 67.7), although this difference was not significant. In moderate to severe glaucoma, diagnostic accuracy of yellow and blue was similar, but blue stimuli showed limited ability to resolve scotomas. Blue mfPOP stimuli, however, may have advantages over yellow in detecting early glaucoma.


Thrombocytopenia secondary to high valproate levels in children with epilepsy.
We reviewed the frequency of valproate-induced thrombocytopenia in children with epilepsy in our institution. Sixty-four (21%) of 306 children taking valproate developed thrombocytopenia. Thirty-two of these 64 patients had at least one platelet count lower than 100 x 10(3)/mm3. Eight patients developed signs of bleeding. Low platelet levels were typically noted in patients with serum valproate levels of over 140 micrograms/mL, and reduction of the medication dose usually resulted in a prompt increase in the number of platelets. Only one patient developed thrombocytopenia unrelated to high serum drug levels, and her platelet count did not improve until the drug was discontinued. Neither the age of the patient nor the use of additional antiepileptic medication correlated with the platelet count. However, duration of valproate use was related. These data suggest that, although valproate may cause thrombocytopenia via more than one mechanism, by far the most common factor is the presence of high valproate levels. Thus, the medication can be safely lowered in most patients with thrombocytopenia rather than discontinued altogether. Platelet counts should probably be monitored more carefully in patients known to have higher drug levels.


Progress in understanding the pathogenesis of Langerhans cell histiocytosis: back to Histiocytosis X?
Langerhans cell histiocytosis (LCH), the most common histiocytic disorder, is characterized by the accumulation of CD1A(+) /CD207(+) mononuclear phagocytes within granulomatous lesions that can affect nearly all organ systems. Historically, LCH has been presumed to arise from transformed or pathologically activated epidermal dendritic cells called Langerhans cells. However, new evidence supports a model in which LCH occurs as a consequence of a misguided differentiation programme of myeloid dendritic cell precursors. Genetic, molecular and functional data implicate activation of the ERK signalling pathway at critical stages in myeloid differentiation as an essential and universal driver of LCH pathology. Based on these findings, we propose that LCH should be re-defined as an inflammatory myeloid neoplasia. Increased understanding of LCH pathogenesis will provide opportunities to optimize and personalize therapy through improved risk-stratification, targeted therapy and assessment of therapy response based on specific molecular features and origin of the pathological myeloid cells.


Ovarian hyperstimulation syndrome prevention strategies: in vitro maturation.
The only reliable way to eliminate the risk of ovarian hyperstimulation syndrome (OHSS) is complete avoidance of gonadotropin ovarian stimulation. It could be argued that in vitro maturation (IVM) of oocytes represents the most effective strategy to prevent OHSS. IVM has been an established treatment option in many centers worldwide for over a decade. The use of IVM and natural cycle in vitro fertilization (IVF) combined with IVM can result in clinical pregnancy rates that compare to those obtained with conventional IVF. The obstetric and perinatal outcomes of IVM pregnancies are similar to those conceived from stimulated IVF or spontaneous conceptions. To date, more than a thousand healthy infants have been born without an increase in fetal abnormalities. Although IVM may not replace standard IVF, it plays an increasingly important role in assisted reproductive technology, especially in the settings of high responders and those patients at risk of OHSS.


Lactoferrin and immunoglobulin contents in camel's milk (Camelus bactrianus, Camelus dromedarius, and Hybrids) from Kazakhstan.
Lactoferrin (Lf) and IgG were estimated in camel's milk from Kazakhstan, where 2 species of camels (Camelus bactrianus, Camelus dromedarius) and their hybrids cohabit. The concentrations of Lf and IgG were determined according to 3 variation factors: region (n = 4), season (n = 4), and species (n = 5; sample 4 was mixed milk and sample 5 was of unknown origin). The mean values in raw camel's milk were 0.229 +/- 0.135 mg/mL for Lf concentration and 0.718 +/- 0.330 mg/mL for IgG concentration. The seasonal effect was the only significant variation factor observed, with the highest values in the spring for Lf and in the winter for IgG. The Lf concentration varied in 1-wk postpartum milk from 1.422 to 0.586 mg/mL. The range in IgG concentration was wide and decreased from 132 to 4.75 mg/mL throughout the 7 d postpartum, with an important drop after parturition. In fermented milk, the lactoproteins are generally hydrolyzed. For milk samples from undefined species, discriminant analyses did not allow the origin of the species to be determined. A slight correlation between Lf and IgG concentrations was observed in raw milk. The values were slightly higher than those reported in cow's milk, but this difference was insufficient to attribute medicinal virtues to camel's milk.


Transition from Dendritic to Cell-like Crystalline Structures in Drying Droplets of Fetal Bovine Serum under the Influence of Temperature.
The desiccation of biofluid droplets leads to the formation of complex deposits which are morphologically affected by the environmental conditions, such as temperature. In this work, we examine the effect of substrate temperatures between 20 and 40 °C on the desiccation deposits of fetal bovine serum (FBS) droplets. The final dried deposits consist of different zones: a peripheral protein ring, a zone of protein structures, a protein gel, and a central crystalline zone. We focus on the crystalline zone showing that its morphological and topographical characteristics vary with substrate temperature. The area of the crystalline zone is found to shrink with increasing substrate temperature. Additionally, the morphology of the crystalline structures changes from dendritic at 20 °C to cell-like for substrate temperatures between 25 and 40 °C. Calculation of the thermal and solutal Bénard-Marangoni numbers shows that while thermal effects are negligible when drying takes place at 20 °C, for higher substrate temperatures (25-40 °C), both thermal and solutal convective effects manifest within the drying drops. Thermal effects dominate earlier in the evaporation process leading, we believe, to the development of instabilities and, in turn, to the formation of convective cells in the drying drops. Solutal effects, on the other hand, are dominant toward the end of drying, maintaining circulation within the cells and leading to crystallization of salts in the formed cells. The cell-like structures are considered to form because of the interplay between thermal and solutal convection during drying. Dendritic growth is associated with a thicker fluid layer in the crystalline zone compared to cell-like growth with thinner layers. For cell-like structures, we show that the number of cells increases and the area occupied by each cell decreases with temperature. The average distance between cells decreases linearly with substrate temperature.


The antibody response to hepatitis B virus vaccination is negatively influenced by the hepatitis C virus viral load in patients with chronic hepatitis C: a case-control study.
The purpose of this work was to evaluate in a case-control study the immunogenicity of a recombinant hepatitis B virus (HBV) vaccine in patients with chronic hepatitis C. Seventy-seven patients with histologically proven chronic hepatitis C without cirrhosis were included in a prospective trial and matched for sex and age to 231 healthy adult subjects. Recombinant HBV vaccine was administered at a dose of 20 microg at months 0, 1 and 2. The definition of 'responder to vaccination' was anti-HBs titre > 10 mIU/ml after the three injections. Forty-nine (63.6%) chronic hepatitis C patients were responders to vaccination, compared with 217 (93.9%) controls (P < 0.0001). After the three injections, anti-HBs titres were 156 +/- 260 and 615 +/- 435 mIU/ml (P < 0.0001), respectively. Chronic hepatitis C patients who were non-responders to vaccination had significantly higher viral load than responders to vaccination. Moreover, a negative correlation was observed between viral load and anti-HBs concentration (r = -0.36, P = 0.003). No significant side effects were observed. There was no effect of vaccination on alanine aminotransferase (ALT) levels and hepatitis C virus (HCV) viral load during or after vaccination. In multivariate analysis, the main predictive factors of response to HBV vaccine were absence of anti-HCV antibodies (OR = 7.65, P < 0.0001), weight < 75 kg (OR = 1.99, P < 0.035), and age < 50 years (OR = 1.58, P < 0.082). Our results suggest that viral load seems to negatively influence the response to HBV vaccine.


Investigation of Needle Characteristics Using an Animal Model for Improved Outcomes in Anterior Chamber Paracentesis.
Background/Aims: The current standard of care to perform an anterior chamber paracentesis involves the use of a multipurpose market needle and syringe. The use of standard needles for this purpose may result in injury to the patient due to increased force with insertion and increased globe displacement during the procedure. This research investigates the current market needle characteristics and the impact of each needle characteristic on force. Methods: Several comparative trials were conducted to evaluate the needles. Needle characteristics of interest were gauge, primary bevel angle, number of bevels in the lancet, and needle hub geometry. Measurements of corneal insertion forces were made using a synthetic thermoplastic polyurethane medium, and bovine and porcine models. Needle safety was investigated with corneal abrasion experiments. Results: Reduced insertion force was observed with lower lancet primary angle. There was no difference based on the number of bevels in the lancet. Rounded hub geometry had minimal distribution to the corneal epithelium. Conclusions: Needle characteristics impact the force needed for needle insertion into the tissue. Since higher force can lead to increased risk and less efficiency during the procedure, reducing this force may improve the outcomes of the procedure. Needle entry can be reduced by designing an improved needle that includes a lower gauge and reduced primary angle of the lancet.


Lateral ventral tegmental area GABAergic and glutamatergic modulation of conditioned learning.
The firing activity of dorso-medial-striatal-cholinergic interneurons (dmCINs) is a neural correlate of classical conditioning. Tonically active, they pause in response to salient stimuli, mediating acquisition of predictive cues/outcome associations. Cortical and thalamic inputs are typical of the rather limited knowledge about underlying circuitry contributing to this function. Here, we dissect the midbrain GABA and glutamate-to-dmCIN pathways and evaluate how they influence conditioned behavior. We report that midbrain neurons discriminate auditory cues and encode the association of a predictive stimulus with a footshock. Furthermore, GABA and glutamate cells form selective monosynaptic contacts onto dmCINs and di-synaptic ones via the parafascicular thalamus. Pathway-specific inhibition of each sub-circuit produces differential impairments of fear-conditioned learning. Finally, Vglut2-expressing cells discriminate between CSs although Vgat-positive neurons associate the predictive cue with the outcome. Overall, these data suggest that each component of the network carries information pertinent to sub-domains of the behavioral strategy.


Neurotoxins: Current Concepts in Cosmetic Use on the Face and Neck--Jawline Contouring/Platysma Bands/Necklace Lines.
The platysma muscle acts as a major depressor in the lower face with subsequent inaesthetic implications. Botulinum toxin-A can be very useful to reverse some of these and this chapter describes how to (1) sharpen the jawline with the Nefertiti Lift, (2) treat anterior neck bands, and (3) soften necklace lines.


[Developments in mass screening for uterine cancer in the past 10 years (1972-1981) in Shimane Prefecture--cell sampling method and the central cytological diagnostic system].
Mass screenings for uterine cancer have been done on 200,000 women in Shimane Prefecture, Japan, from 1972-1981. Up to 1978, a cotton-tipped applicator was used for sample procurement and since that time a wooden spatula type instrument has been used. A central, cytological diagnostic system has been used since 1979. The cytology activity index (CAI) was about 90 each year. The rate of second examination performed is about 60% for women requiring an accurate examination. Cancer detection rates increased from 0.05% to 0.12%, the false negative rate decreased, cytological and histological findings were in close parallel and the mortality rates have decreased. These positive results are attributed to the use of the wooden spatula and central diagnostic systems. By the mass screening for uterine cancer during these 10 years, 81 women were detected as having carcinoma in situ and 107 women as having invasive carcinoma in the histological findings. The number of first screenings has decreased gradually, but the number examined 6 times or more has increased. These results include that same women have tended to undergo the mass screening examination. In women over 50 y.o., particularly those 60 or over, the number screened was low, yet the incidence of invasive cancer exceeded that in other groups.


A rare case of hypomelanosis of Ito with enlargement of Virchow-Rabin spaces in a 10-year-old child with symptoms of seizures.
Hypomelanosis of Ito (HI) syndrome is a complex neuro-dermatological disorder that affects many organs in the body, including the skin, brain, eyes, and skeleton. This disease has been reported to present with seizures in a few rare cases. Seizures are seen in all age groups but are more common in children and the elderly. Virchow-Robin spaces (VRSs) are spaces around small arteries and the arteries that pierce the surface of the brain and are spread throughout the rest of the brain. As individuals age, the number and size of VRSs increase. A relationship between dilated VRSs and neuropsychiatric disorders has been observed above a 2 mm threshold. The patient is a 10-year-old child who was referred to the neurology ward of Imam Hossein Children's Hospital in Isfahan about 2.5 months ago due to seizures. The last seizure occurred four days before the visit, and the patient was sent for a brain computed tomography (CT) scan, which revealed diffuse bilateral hypopigmented lesions in the brain's white matter. The results of the para-clinical tests were relatively unremarkable. In the early stages of hospitalization, the child received treatment such as fluid therapy and anticonvulsant drugs to stabilize their vital condition. The patient's para-clinical tests, including brain CT, electroencephalogram, complete blood count, liver function test, and magnetic resonance imaging, showed the presence of HI syndrome and bilateral diffuse hypopigmented lesions in the white matter.


Fetal hemoglobin in sickle cell anemia: The Arab-Indian haplotype and new therapeutic agents.
Fetal hemoglobin (HbF) has well-known tempering effects on the symptoms of sickle cell disease and its levels vary among patients with different haplotypes of the sickle hemoglobin gene. Compared with sickle cell anemia haplotypes found in patients of African descent, HbF levels in Saudi and Indian patients with the Arab-Indian (AI) haplotype exceed that in any other haplotype by nearly twofold. Genetic association studies have identified some loci associated with high HbF in the AI haplotype but these observations require functional confirmation. Saudi patients with the Benin haplotype have HbF levels almost twice as high as African patients with this haplotype but this difference is unexplained. Hydroxyurea is still the only FDA approved drug for HbF induction in sickle cell disease. While most patients treated with hydroxyurea have an increase in HbF and some clinical improvement, 10 to 20% of adults show little response to this agent. We review the genetic basis of HbF regulation focusing on sickle cell anemia in Saudi Arabia and discuss new drugs that can induce increased levels of HbF.


Rituximab for Steroid-Dependent Minimal Change Disease in Adults: Is It Time for a Change?
Minimal change disease (MCD) is a common cause of nephrotic syndrome, and steroid treatment is usually effective at the expense of adverse effects and frequent relapses. Rituximab, a monoclonal antibody against cluster of differentiation (CD)20 B-lymphocytes, leads to depletion of B-cells and has been frequently used to treat relapsing MCD in children. The efficacy of rituximab in treating adult MCD is limited. We report our experience with the use of rituximab for adult biopsy-proven MCD. Our series includes four adult patients (two males and two females), aged 22-80 years, treated with rituximab. All four patients achieved a complete remission with rituximab which lasted from 12 to 19 months. No adverse events from rituximab were observed. This shows the remarkable efficacy of rituximab in the treatment of minimal change disease in adults and may be preferred in patients at high risk for the development of adverse events from corticosteroids.


Varying impact of co-morbid conditions on self-harm resulting in mortality in Australia.
Research has associated some chronic conditions with self-harm and suicide. Quantifying such a relationship in mortality data relies on accurate death records and adequate techniques for identifying these conditions. This study aimed to quantify the impact of identification methods for co-morbid conditions on suicides in individuals aged 30 years and older in Australia and examined differences by gender. A retrospective examination of mortality records in the National Coronial Information System (NCIS) was conducted. Two different methods for identifying co-morbidities were compared: International Statistical Classification of Diseases and Related Health Problems, 10th Revision (ICD-10) coded data, which are provided to the NCIS by the Australian Bureau of Statistics, and free-text searches of Medical Cause of Death fields. Descriptive statistics and χ2 tests were used to compare the methods for identifying co-morbidities and look at differences by gender. Results showed inconsistencies between ICD-10 coded and coronial reports in the identification of suicide and chronic conditions, particularly by type (physical or mental). There were also significant differences in the proportion of co-morbid conditions by gender. While ICD-10 coded mortality data more comprehensively identified co-morbidities, discrepancies in the identification of suicide and co-morbid conditions in both systems require further investigation to determine their nature (linkage errors, human subjectivity) and address them. Furthermore, due to the prescriptive coding procedures, the extent to which medico-legal databases may be used to explore potential and previously unrecognised associations between chronic conditions and self-harm deaths remains limited.


A preclinical and clinical study of mycophenolate mofetil in pancreatic cancer.
A high throughput screening for anticancer activity of FDA approved drugs identified mycophenolic acid (MPA), an inhibitor of inositol monophosphate dehydrogenase (IMPDH) as an active agent with an antiangiogenesis mode of action. Exposure of pancreatic cancer cell lines to MPA resulted in growth inhibition and reduced the expression of VEGF that was reversed by supplementing the media with guanosine supporting and IMPDH-dependant mechanism. In preclinical in vivo study, MPA showed a moderate inhibition of tumor growth in a panel of 6 human derived pancreatic cancer xenografts but reduced the expression of VEGF. To investigate the effects of MPA in human pancreatic cancer, a total of 12 patients with resectable pancreatic cancer (PDA) received increasing doses of mycophenolate mofetil (MMF) in cohorts of 6 patients each from 5-15 days prior to surgical resection. Treatment was well tolerated with one episode of grade 1 muscle pain, one episode of grade 2 lymphopenia (2 gr/day dose) and one episode of grade 2 elevantion in LFT (all in the 2 gr./day dose). Patients recovered from surgery uneventfully with no increased post-operative complications. Assessment of CD31, VEGF, and TUNEL in resected specimens compared to a non treated control of 6 patients showed no significant variations in any of the study endpoints. In conclusion, this study shows the feasibility of translating a preclinical observation to the clinical setting and to explore a drug mechanism of action in patients. MPA, however, did not show any hints of antiangiogenesis of anticancer clinical activity questioning if this agent should be further developed in PDA.


Ultrafast hole transfer mediated by polaron pairs in all-polymer photovoltaic blends.
The charge separation yield at a bulk heterojunction sets the upper efficiency limit of an organic solar cell. Ultrafast charge transfer processes in polymer/fullerene blends have been intensively studied but much less is known about these processes in all-polymer systems. Here, we show that interfacial charge separation can occur through a polaron pair-derived hole transfer process in all-polymer photovoltaic blends, which is a fundamentally different mechanism compared to the exciton-dominated pathway in the polymer/fullerene blends. By utilizing ultrafast optical measurements, we have clearly identified an ultrafast hole transfer process with a lifetime of about 3 ps mediated by photo-excited polaron pairs which has a markedly high quantum efficiency of about 97%. Spectroscopic data show that excitons act as spectators during the efficient hole transfer process. Our findings suggest an alternative route to improve the efficiency of all-polymer solar devices by manipulating polaron pairs.


Hierarchical networks of redox-active reduced crumpled graphene oxide and functionalized few-walled carbon nanotubes for rapid electrochemical energy storage.
Crumpled graphene is known to have a strong aggregation-resistive property due to its unique 3D morphology, providing a promising solution to prevent the restacking issue of graphene based electrode materials. Here, we demonstrate the utilization of redox-active oxygen functional groups on the partially reduced crumpled graphene oxide (r-CGO) for electrochemical energy storage applications. To effectively utilize the surface redox reactions of the functional groups, hierarchical networks of electrodes including r-CGO and functionalized few-walled carbon nanotubes (f-FWNTs) are assembled via a vacuum-filtration process, resulting in a 3D porous structure. These composite electrodes are employed as positive electrodes in Li-cells, delivering high gravimetric capacities of up to ∼170 mA h g(-1) with significantly enhanced rate-capability compared to the electrodes consisting of conventional 2D reduced graphene oxide and f-FWNTs. These results highlight the importance of microstructure design coupled with oxygen chemistry control, to maximize the surface redox reactions on functionalized graphene based electrodes.


Post-colonoscopy colorectal cancer (PCCRC) rates vary considerably depending on the method used to calculate them: a retrospective observational population-based study of PCCRC in the English National Health Service.
Post-colonoscopy colorectal cancer (PCCRC) is a key quality indicator of colonoscopy. This study compares methods for defining PCCRC rates, proposes a new method of calculating them and quantifies them across the English National Health Service (NHS). This retrospective observational population-based study involved all individuals with a first primary diagnosis of colorectal cancer made between 2001 and 2010 and treated in the English NHS. Previously published methods for deriving PCCRC rates were applied to the linked routine health data for this population to investigate the effect on the rate. A new method, based on the year of the colonoscopy rather than colorectal cancer diagnosis, was then used to calculate PCCRC rates. Of 297,956 individuals diagnosed with colorectal cancer, a total of 94,648 underwent a colonoscopy in the 3 years prior to their diagnosis. The application of the published methods and exclusion criteria to the dataset produced significantly different PCCRC rates from 2.5% to 7.7%. The new method demonstrates that PCCRC rates within 3 years of colonoscopy (without exclusions) decreased in the English NHS over 8 years, falling from 10.6% to 7.3% for colonoscopies performed in 2001 and 2007 respectively. The method used to determine PCCRC rates significantly affects findings with potential to substantially underestimate rates. To enable international benchmarking there needs to be a standardised method for defining PCCRC. This study proposes a new methodology using colonoscopy as a denominator and between 2001 and 2007 this method indicated an 8.6% PCCRC rate across the English NHS. It also demonstrated PCCRC rates have fallen over time.


HSP90 expression is associated with outcome in pulmonary carcinoid tumor patients.
Pulmonary carcinoids (PCs) are rare tumors that account for <2% of all lung cancer cases. Patients who undergo resection for PC tumors generally have a favorable prognosis, but there is a risk for late recurrence and distant metastasis. The objective of this study was to identify biomarkers for PC tumors using RNA sequencing and immunohistochemistry. A total of 128 formalin-fixed, paraffin-embedded PC tumor samples from patients surgically treated at Helsinki University Hospital between 1990 and 2013 were analyzed in the study. RNA sequencing was first used to detect genes with higher expression in specific histological subtypes and metastatic and nonmetastatic tumors than in adjacent lung tissue. The diagnostic potential of the biomarkers was assessed using immunohistochemistry. Through gene expression analysis, HSP90AB1 expression was found to be significantly elevated in metastatic PC tumors (P<0.0001). The paralog of the gene, HSP90AA1, was also overexpressed, but the finding was not statistically significant. Through immunohistochemical analysis, HSP90 protein expression was found to be associated with shorter disease-specific survival (DSS) (P=0.009) and increased risk of disease-specific death [hazard ratio (HR) 6.4, 95% confidence interval (CI): 1.3-31.8]. This study confirms that HSP90 has a prognostic role in PC tumors and that inhibition of HSP90 may possess therapeutic potential in the management of PC tumor patients in the future.


MiR-10b inhibits migration and invasion of pancreatic ductal adenocarcinoma via regulating E2F7.
Abnormal microRNAs (miRNAs) expression is closely related to the development and poor prognosis of pancreatic ductal adenocarcinoma (PDAC). We aimed to elucidate the invasive mechanism and clinical significance of miR-10b in PDAC. The RNA sequence data of pancreatic cancer were extracted from the TCGA database. R packages were performed to analyze the differential expression of RNAs. TargetScan, picTar, and miRanda were used to predict the target gene of miRNA. The expression level of the selected candidate was tested by western blot and RT-PCR in PDAC cells and tissues. Scrape and Transwell assays were determined the effect of candidate molecules on cell migration and invasion. The gain of function and loss of function was achieved by co-culture with mimics and vector. Luciferase reporters were generated based on the psiCHECK2 vector. The relative luciferase activity was measured with the Dual-Luciferase Reporter Assay System and Infinate M200 PRO microplate reader. Based on the TCGA data and bioinformatics analysis, we obtained seven differentially expressed miRNAs. Both TCGA data and our center clinical date indicated that miR-10b was contributed to the poor survival of PDAC. Based on the target gene prediction database, we found that E2F7 was a target mRNA of miR-10b. In subsequent experiments in molecular biology, miR-10b expression was downregulated in PDAC cells and tissues, while E2F7 was upregulated. Scrape and Transwell assay indicated that miR-10b could inhibit the invasion and migration of PDAC. MiR-10b was confirmed to be by the E2F7 targeting site by dual-luciferase report. Moreover, rescue experiments prove that miR-10b could inhibit the invasion and migration of PDAC cells by regulating E2F7 expression. Our results suggest that miR-10b could inhibit the progression of PDAC by regulating E2F7 expression and acts as an independent prognostic risk factor for PDAC.


Differential temporal development of alveoli and the alveolar capillary network in the postnatal rat lung.
Quantitative data about the internal lung structure are needed to better understand normal and pathological lung development. Aberrant lung development causes deficits in alveolar and microvascular development; however, the normal temporal relationship between these processes is still not fully understood. We hypothesized that alveolar and capillary development show a differential time pattern. Lungs of rats aged 3, 7, 14, 21 days (d) or 3 mo (n = 8-10 each) were fixed by vascular perfusion and processed for light microscopy. Using design-based stereology number, the surface area and volume of alveoli, septal capillaries, and alveolar septa were quantified. The total number and the total volume of alveoli increased progressively during postnatal development. Interestingly, the numerical density of capillary loops was significantly higher in 14- and 21-d-old rats than before or after this age, causing a duplication of the total number of capillary loops between 1 and 2 wk of age. The mean thickness of alveolar septa started to decline slightly at the age of 14d and more pronounced at later stages. Although the septal epithelial surface area increased in proportion to alveolar number during the first 3 wk, the capillary endothelial surface area grew only slightly compared with the number of capillaries. In conclusion, the number of elements composing the alveolar capillary network expands massively during the first two postnatal weeks and exceeds the formation of alveoli. The thinning of the alveolar septa during further development suggests a reduction of the capillary network during alveolarization.


Epidemic cycles in agricultural populations: a cross-cultural study.
A cross-cultural analysis of mortality patterns is of interest to biological anthropologists and genetic epidemiologists. In this paper, we examine four agricultural populations from Costa Rica, Hungary, and the United States in order to determine if they suffered from a cyclical distribution of epidemics. When possible, we look at the mortality time series of adults and children separately. Of the 2 series, only 2 show significant epidemic cycles. Both are in the Hungarian groups and both affect subadults. Otherwise, the Costa Rica, U.S., and adult series of the Hungarian groups do not show any periodicity of mortality peaks. Our results indicate that epidemic cycles are not as ubiquitous in small agricultural groups as the literature would suggest.


Metformin modulates immune cell infiltration into the kidney during unilateral ureteral obstruction in mice.
Metformin is today the first choice treatment for type-2 diabetes, but has also protective effects in several renal disease models. Previously, we have demonstrated that the protective effects in response to unilateral ureteral obstruction (UUO) are independent of organic cation transporters (OCTs), the transporters responsible for the metformin uptake into the renal cells. The mechanisms behind the renoprotective effects are incompletely understood, but our previous results indicate that the renoprotective effects at least partly could be dependent on actions of metformin outside the renal cells. In this study, we investigate whether the renoprotective effects of metformin can be mediated via systemic immunomodulatory actions. We demonstrated that metformin can affect the immune system in the kidney as well as in the peripheral blood and spleen following UUO. UUO kidneys showed infiltration of immune cells including monocytes, B cells, and T cells, but metformin limited infiltration of all cell types. UUO animals had increased spleen sizes, but this increase was attenuated by metformin. Metformin treatment surprisingly resulted in a higher proportion of monocytes with infiltratory capacity 7 days after UUO. Other studies have suggested that metformin regulates monocyte maturation through signal transducer and activator of transcription 3 (STAT3) activation, as also indicated by our results. In conclusion, our results demonstrate that metformin limits the infiltration of immune cells into the kidney, as well as modulates immune cell composition at a systemic level.


Naturally occurring mouse antibodies against T-cell-secreted chondroitin sulphate proteoglycan.
Stimulated T lymphocytes and certain T-cell hybridomas secrete molecules capable of inducing B-lymphocyte proliferation and differentiation. It has been shown recently that one such B-cell stimulatory factor is associated with chondroitin sulphate proteoglycan (CSPG) and was designated T-cell proteoglycan fraction, or T-PGF. We report here that mouse spleen cells cultured at high densities or stimulated with lipopolysaccharide (LPS) at low cell densities secrete antibodies directed against T-PGF. Such antibodies react primarily with the CSPG component of T-PGF and can inhibit the induction of plaque-forming cells (PFC) by T-PGF. By fusing high-density cultures of unstimulated mouse spleen cells with the myeloma P3 x 63AG8.653, several anti-T-PGF (CSPG) hybridomas were derived that exhibited activities identical to anti-T-PGF (CSPG) obtained from high-density spleen cell culture supernatants. The role that these spontaneously secreted autoantibodies may play in immunoregulation is discussed.


Development of an Injectable Calcium Phosphate/Hyaluronic Acid Microparticles System for Platelet Lysate Sustained Delivery Aiming Bone Regeneration.
Despite the biocompatibility and osteoinductive properties of calcium phosphate (CaP) cements their low biodegradability hampers full bone regeneration. Herein the incorporation of CaP cement with hyaluronic acid (HAc) microparticles loaded with platelet lysate (PL) to improve the degradability and biological performance of the cements is proposed. Cement formulations incorporating increasing weight ratios of either empty HAc microparticles or microparticles loaded with PL (10 and 20 wt%) are developed as well as cements directly incorporating PL. The direct incorporation of PL improves the mechanical properties of the plain cement, reaching values similar to native bone. Morphological analysis shows homogeneous particle distribution and high interconnectivity between the HAc microparticles. The cements incorporating PL (with or without the HAc microparticles) present a sustained release of PL proteins for up to 8 d. The sustained release of PL modulates the expression of osteogenic markers in seeded human adipose tissue derived stem cells, thus suggesting the stimulatory role of this hybrid system toward osteogenic commitment and bone regeneration applications.


Calcium negatively regulates secretion from dense granules in Toxoplasma gondii.
Apicomplexan parasites including Toxoplasma gondii and Plasmodium spp. manufacture a complex arsenal of secreted proteins used to interact with and manipulate their host environment. These proteins are organised into three principle exocytotic compartment types according to their functions: micronemes for extracellular attachment and motility, rhoptries for host cell penetration, and dense granules for subsequent manipulation of the host intracellular environment. The order and timing of these events during the parasite's invasion cycle dictates when exocytosis from each compartment occurs. Tight control of compartment secretion is, therefore, an integral part of apicomplexan biology. Control of microneme exocytosis is best understood, where cytosolic intermediate molecular messengers cGMP and Ca2+ act as positive signals. The mechanisms for controlling secretion from rhoptries and dense granules, however, are virtually unknown. Here, we present evidence that dense granule exocytosis is negatively regulated by cytosolic Ca2+ , and we show that this Ca2+ -mediated response is contingent on the function of calcium-dependent protein kinases TgCDPK1 and TgCDPK3. Reciprocal control of micronemes and dense granules provides an elegant solution to the mutually exclusive functions of these exocytotic compartments in parasite invasion cycles and further demonstrates the central role that Ca2+ signalling plays in the invasion biology of apicomplexan parasites.


The indispensable role of CCR5 for in vivo suppressor function of tumor-derived CD103+ effector/memory regulatory T cells.
CD103 is a marker for identification of effector/memory regulatory T cells (Tregs). CD103(+) Tregs are potent suppressors of tissue inflammation in several infectious diseases, autoimmune diseases, and cancers. However, the underlying mechanisms for this potent suppression ability remain unclear. The current study was designed to clarify this issue. Unexpectedly, we found both CD103(+) and CD103(-) Tregs had similar suppression capacity in vitro. We then chose a murine tumor model for investigation of the in vivo behavior of these Tregs. The suppression ability in vivo against the anti-tumor ability of CD8(+) T cells was restricted to CD103(+) Tregs although both Tregs had equal in vitro suppression ability. In addition, CD103(+) Tregs expressed significantly higher levels of CCR5 than those of CD103(-) Tregs and accumulated more in tumors than did CD103(-) Tregs. Furthermore, blockade of CCR5 signaling, either by CCR5(-/-)CD103(+) Tregs or by CCL5 knockdown tumor, could reduce the migration of CD103(+) Tregs into tumors and impair their in vivo suppression ability. In conclusion, these results indicate that the potent in vivo suppression ability of CD103(+) Tregs is due to the tissue-migration ability through CCR5 expression.


Measurement and differentiation of the cellular infiltrate in experimental toxic contact dermatitis.
Toxic (irritant) contact dermatitis was elicited by epicutaneous application of dinitrochlorobenzene (DNCB) and croton oil in unsensitized guinea pigs. The course of the skin reaction was studied with the naked eye, low-power microscopy, and a method based on counting of infiltrating cells in the upper corium. A weakly toxic dose of DNCB (100 microgram/cm2) gave marked erythema and moderate swelling, more pronounced 6 h after application of the DNCB than at 24 h or 48 h. A significant increase in mononuclear cells in particular but also in neutrophil and eosinophil granulocytes was noted in the upper corium. A more strongly toxic dose (500 microgram/cm2) gave a similar visible reaction, this too most marked at 6 h, but here there was an increase in neutrophil granulocytes in particular. Over and above predominant mononuclear-cell infiltration, croton oil (10 microgram/cm2) caused a slight increase in basophil cells. The reaction thus resembled a contact allergic reaction. In the light of earlier findings in allergic contact reactions the results suggest that weak stimuli, toxic or allergenic, elicit a non-specific skin response. With stronger stimulation the histological picture is modified and the cellular response acquires a pattern characteristic of toxic or allergic contact dermatitis.


National Sporting Organisation policies: A health promotion opportunity?
The objective was to identify whether National Sporting Organisations (NSOs) have policy documentation on healthy behaviours (smokefree, sun-protection, healthy food/beverages and alcohol) and, for organisations with such documentation, whether this was in-line with current scientific evidence of past best practice in cancer prevention. This cross-sectional policy analysis study was performed September to December 2018 in Aotearoa/New Zealand. A content analysis was undertaken using NSO policy documents matched against a framework of key indicators for best practice within health behaviours of interest. Data analysis of the policy process was undertaken through key informant telephone interviews with NSO staff using semi-structured qualitative interviews. Of 96 NSOs, nearly half (49%) mentioned smokefree at least once in one of their policy documents, and 47% had an alcohol policy, although in both instances the policies lacked comprehensiveness. Two NSOs had a reasonably comprehensive sun protection policy. Seventeen had at least one specific nutrition policy/guideline. The contents of the latter were primarily related to short-term athletic performance rather than non-communicable disease prevention, specifically promoting hydration during sports participation, and food and nutrition to support sporting performance. Two NSOs had policies relating to the promotion of healthy food/nutrition more widely. For some NSOs, the lack of health-related policies was not a conscious choice but just not considered previously. Other NSOs reported they lacked resources or had other priorities. Although this study clearly demonstrates that many NSOs lack adequate health-related policies, this is not necessarily a conscious choice, but the result of a lack of resources, other priorities, or just that they had not considered developing policies in these areas. A number expressed support for these types of policies although it was apparent that some, particularly smaller NSOs, would require assistance in policy template development. It seems probable that the development of health-related policies will only occur if partner agencies become involved.


Impulsivity and adolescent substance use: rashly dismissed as "all-bad"?
The initial use of illicit drugs and alcohol typically occurs during adolescence. Individual differences in impulsivity and related constructs are consistently identified as key factors in the initiation and later problematic use of substances. Consequently, impulsivity is generally regarded as a negative trait; one that conveys only risk. However, what is often overlooked in addiction science is the positive role facets of trait impulsivity can play in everyday life and adaptive functioning. The following review aims to summarize recent advances in the psychobiology of impulsivity, including current perspectives on how it can convey risk for substance misuse. The review will also consider the importance of adolescence as a phase of life characterized by substantial neurodevelopment and natural increases in impulsivity. Uniquely, the review aims to reframe thinking on adolescent impulsivity to include the positive with the negative, and discuss how such thinking can benefit efforts for early intervention and future research.


MRD and Plasma Cell Dynamics after CAR T-cell Therapy in Myeloma.
In this issue, Paiva and colleagues characterize the dynamics of minimal residual disease (MRD) and clinical responses during chimeric antigen receptor (CAR) T-cell therapy of relapsed/refractory multiple myeloma. Although both correlate with prolonged progression-free survival, MRD is reached faster in the bone marrow than complete response in peripheral blood; consequently, the study addresses the need for future guidelines to explore new MRD-negative definitions that are independent of the monoclonal (M) protein to overcome this limitation, particularly in clinical trials using early depth of response as an endpoint. See related article by Paiva et al., p. 365 (1).


Contactless remote monitoring of sleep: evaluating the feasibility of an under-mattress sensor mat in a real-life deployment.
Sleep is so important, particularly for the elderly. The lack of sleep may increase the risk of cognitive decline. Similarly, it may also increase the risk of Alzheimer's disease. Nonetheless, many people underestimate the importance of getting enough rest and sleep. In-laboratory polysomnography is the gold-standard method for assessing the quality of sleep. This method is considered impractical in the clinical environment, seen as labour-intensive and expensive owing to its specialised equipment, leading to long waiting lists. Hence, user-friendly (remote and non-intrusive) devices are being developed to help patients monitor their sleep at home. In this paper, we first discuss commercially-available non-wearable devices that measure sleep, in which we highlight the features associated with each device, including sensor type, interface, outputs, dimensions, power supply, and connectivity. Second, we evaluate the feasibility of a non-wearable device in a free-living environment. The deployed device comprises a sensor mat with an integrated micro-bending multimode fibre. Raw sensor data were gathered from five senior participants living in a senior activity centre over a few to several weeks. We were able to analyse the participants' sleep quality using various sleep parameters deduced from the sensor mat. These parameters include the wake-up time, bedtime, the time in bed, nap time. Vital signs, namely heart rate, respiratory rate, and body movements, were also reported to detect abnormal sleep patterns. We have employed pre-and post-surveys reporting each volunteer's sleep hygiene to confirm the proposed system's outcomes for detecting the various sleep parameters. The results of the system were strongly correlated with the surveys for reporting each sleep parameter. Furthermore, the system proved to be highly effective in detecting irregular patterns that occurred during sleep.


[Renal involvement in ankylosing spondylitis: concerning 210 cases].
To define the epidemiology, clinical, biological and histological features of renal diseases in ankylosing spondylitis, ginving special attention to unusual forms. We retrospectively reviewed the medical record of 28 cases with renal involvement among 210 cases of ankylosing spondylitis seen over a 27 year period who met the Amor criteria. Twenty-eight of 210 patients (13,3%) presented one or more signs of renal involvement: macroscopic hematuria (4 patients), microscopic hematuria (8 patients), proteinuria (15 patients), nephrotic syndrome (6 patients), decreased renal function (13 patients). Secondary renal amyloidosis and nephrolithiasis (8 patients) were the most common cause of renal involvement in ankylosing spondylitis followed by IgA nephropathy (3 patients). The funding of renal abnormalities in 13,3% of our patients suggests that in this illness evidence of renal involvement should be actively investigated in ankylosing spondylitis.


Alterations in the immunoreactivity of laminin, type IV collagen and α3β1 integrin in diabetic rat ovarian follicles.
In order to determine the possible effects of diabetes, we aimed to investigate the expression of extracellular matrix proteins in the theca and granulosa layers in different follicular stages. Thirty-two adult Wistar albino male rats were divided into 4 groups as control and sampled groups. Four, eight and twelve weeks after inducing diabetes with an intraperitoneal injection of streptozotocin (40 mg/kg), the expressions of laminin, type IV collagen and α3β1 integrin in ovarian tissues were evaluated by immunohistochemical method. In our study, in the first month of diabetes, a significant increase was observed in laminin, type IV collagen and α3β1 integrin expressions in all follicle types compared to the control group in both the theca and granulosa layers. Laminin and type IV collagen immunoreactivity tended to increase in D2 and D3 groups also. Integrin expression did not change in the newly formed follicles in the D2 and D3 groups, however, it tended to change and increase in the developing follicles. The changes in the expression of laminin, type IV collagen and α3β1 integrin, which are the extracellular matrix proteins in the follicle, along with diabetes, show that diabetes plays a role in the regulation of follicular development (Tab. 4, Fig. 36, Ref. 29).


Electricity generation through degradation of organic matters in medicinal herbs wastewater using bio-electro-Fenton system.
In the present study, the potential application of the bio-electro-Fenton (BEF) process for the treatment of medicinal herbs wastewater in a mediator-less microbial fuel cell (MFC) system is investigated. This process is operated in a dual-chamber MFC with anaerobic seed sludge as biocatalyst in an anode chamber under conditions of neutral pH, an aerobic cathode chamber equipped with a Fe@Fe2O3/graphite composite cathode and a Nafion membrane as a separator. The performance of the MFC is determined in three different mixed liquor suspended solids (MLSS) loadings, Nafions (112, 115) and a salt bridge in an air-cathode BEF process, in terms of power generation, chemical oxygen demand (COD) removal efficiency, columbic and energy efficiencies. Under optimal conditions, the batch experiment results show that the cathode chamber of the BEF reactor, equipped with Nafion 112 and inoculated with seed sludge at 3000 mg L(-1) MLSS concentration, produces the maximum power density of 49.76 mW m(-2), 0.56 mg L(-1) and 29 mol L(-1) of H2O2 and Fe(2+), respectively. Under these conditions, the MFC achieves COD removal 78.05% in the anaerobic anode chamber and 84.02% as a result of aerobic processes from the air-cathode BEF chamber, whilst the maximum voltage εcb and εE values are 600 mV, 4.09% and 1.37%, respectively.


Plasma fasting and nonfasting triglycerides and high-density lipoprotein cholesterol in atherosclerotic stroke: different profiles according to low-density lipoprotein cholesterol.
Although low-density lipoprotein cholesterol (LDL-C) is the main lipid target for cardiovascular risk reduction, recent studies suggest that other lipid indicies are also associated with vascular events. We hypothesized that the association of triglycerides (TG) and high-density lipoprotein cholesterol (HDL-C) with atherosclerotic stroke (AS) differs depending on LDL-C levels. Data prospectively collected on subjects admitted with acute ischemic stroke to a university medical center were analyzed. We divided the patients into AS and non-atherosclerotic stroke (NAS) groups and independent association of lipid parameters and genetic influences of apolipoprotein A5 (ApoA5) polymorphisms with AS were evaluated. Of 268 patients, 160 (59.7%) were classified with AS and 108 (40.3%) were classified with NAS. Vascular risk factors were more prevalent in AS patients than in those with NAS; additionally, AS patients' anthropometric indexes and laboratory findings showed that they were prone to atherosclerosis. AS was independently associated with fasting TG (OR per 10 mg/dL increase, 1.38; 95% CI, 1.16-1.64; OR for highest vs. lowest tertile, 12.85; 95% CI, 3.31-49.85), HDL-C (OR per 10 mg/dL increase, 0.61; 95% CI, 0.42-0.88; OR for lowest vs. highest tertile, 4.28; 95% CI, 1.16-15.86), and nonfasting TG (OR per 10 10 mg/dL increase, 1.25; 95% CI, 1.11-1.42; OR for highest vs. lowest tertile, 8.20; 95% CI, 1.98-33.88) only among patients with LDL <100 mg/dL. No interaction was observed between fasting and nonfasting TG and ApoA5 polymorphisms. In conclusion, fasting and nonfasting TG and HDL-C were associated with AS only when patients had low levels of LDL-C. Non-LDL-C may have an additional role in addition to the LDL-C levels in AS development.


Reducing Alignment Time Complexity of Ultra-Large Sets of Sequences.
The alignment of three or more protein or nucleotide sequences is known as Multiple Sequence Alignment problem. The complexity of this problem increases exponentially with the number of sequences; therefore, many of the current approaches published in the literature suffer a computational overhead when thousands of sequences are required to be aligned. We introduce a new approach for dealing with ultra-large sets of sequences. A two-level clustering method is considered. The first level clusters the input sequences by using their biological composition, that is, the number of positive, negative, polar, special, and hydrophobic amino acids. In the second level, each cluster is divided into different clusters according to their similarity. Then, each cluster is aligned by using any method/aligner. After aligning the centroid sequences of each second-level cluster, we extrapolate the new gaps to each cluster of sequences to obtain the final alignment. We present a study on biological data with up to ∼100,000 sequences, showing that the proposed approach is able to obtain accurate alignments in a reduced amount of time; for example, in >10,000 sequences datasets, it is able to reduce up to ∼45 times the required runtime of the well-known Kalign.


The Features of Copper Metabolism in the Rat Liver during Development.
Strong interest in copper homeostasis is due to the fact that copper is simultaneously a catalytic co-factor of the vital enzymes, a participant in signaling, and a toxic agent provoking oxidative stress. In mammals, during development copper metabolism is conformed to two types. In embryonic type copper metabolism (ETCM), newborns accumulate copper to high level in the liver because its excretion via bile is blocked; and serum copper concentration is low because ceruloplasmin (the main copper-containing protein of plasma) gene expression is repressed. In the late weaning, the ETCM switches to the adult type copper metabolism (ATCM), which is manifested by the unlocking of copper excretion and the induction of ceruloplasmin gene activity. The considerable progress has been made in the understanding of the molecular basis of copper metabolic turnover in the ATCM, but many aspects of the copper homeostasis in the ETCM remain unclear. The aim of this study was to investigate the copper metabolism during transition from the ETCM (up to 12-days-old) to the ATCM in the rats. It was shown that in the liver, copper was accumulated in the nuclei during the first 5 days of life, and then it was re-located to the mitochondria. In parallel with the mitochondria, copper bulk bound with cytosolic metallothionein was increased. All compartments of the liver cells rapidly lost most of their copper on the 13th day of life. In newborns, serum copper concentration was low, and its major fraction was associated with holo-Cp, however, a small portion of copper was bound to extracellular metallothionein and a substance that was slowly eluted during gel-filtration. In adults, serum copper concentration increased by about a factor of 3, while metallothionein-bound copper level decreased by a factor of 2. During development, the expression level of Cp, Sod1, Cox4i1, Atp7b, Ctr1, Ctr2, Cox17, and Ccs genes was significantly increased, and metallothionein was decreased. Atp7a gene's activity was fully repressed. The copper routes in newborns are discussed.


[Possible relation between viruses and oromaxillofacial tumors. I. Demonstration of herpes antigens and anti-herpes antibodies].
Herpes virus type 1 and 2 antigens were detected in cells originating from malignant tumors with oromaxillofacial localization. A higher incidence of type 1 antigens was noted, as compared to the type 2. Investigated antigens were detected more frequently in the tumors of ectodermal origin. Antiherpesvirus FC antibodies were found in 74.5% of the tumor bearing subjects, but only in 22.3% of the controls.


Ultrasensitive Detection of DNA and Ramos Cell Using In Situ Selective Crystallization Based Quartz Crystal Microbalance.
Herein we introduce the first successful assay of biomolecule by in situ selective crystallization based quartz crystal microbalance (QCM). Selective crystallization of CaCO3 on QCM sensor surface was utilized as an efficient mass amplification strategy and enhanced the sensitivity of QCM significantly. High specificity is guaranteed by the cooperation of two functional groups: -N(CH3)3 and -COOH. Passivation of sensor surface is realized by self-assembly of -N(CH3)3, which effectively inhibited the nonspecific crystallization. The DNA target is detected through hybridization of probe DNA labeled with -COOH, which can effectively promot the in situ surface crystallization of CaCO3. The concentration of target DNA is reflected by the frequency shift of QCM which is directly induced by the surface crystallization. The selective crystallization based QCM platform is simple, straightforward, high sensitive, and high specific. We demonstrate the excellent LOD (2 aM DNA) and a linear range of 10aM to 1 nM for DNA. Detection of Ramos cells are also realized with a LOD of five cells and a linear range of 5-6000 cells.


Cranial computed tomography in the resuscitated patient with cardiac arrest.
The incidence of out-of-hospital and in-hospital cardiorespiratory arrest from all causes in the United States occurs not infrequently. Postresuscitation care should include the identification of the inciting arrest event as well as therapy tailored to support the patient and treat the primary cause of the decompensation. The application of one particular testing modality, cranial computed tomography (CT) of the head, has not yet been determined. We undertook an evaluation of the use of head CT in patients who were resuscitated from cardiac arrest. Prehospital (emergency medical services), ED, and hospital records were reviewed for patients of all ages with cardiorespiratory arrest over a 4-year period (July 1996-June 2000). Information regarding diagnosis, management, and outcome was recorded. The results of cranial CT, if performed, and any apparent resulting therapeutic changes were recorded. Patients with a known traumatic mechanism for the cardiorespiratory arrest were excluded. A total of 454 patients (mean age 58.3 years with 60% male) with cardiorespiratory arrest were entered in the study with 98 (22%) individuals (mean age 58.5 years with 53% male) undergoing cranial CT. Arrest location was as follows: emergency medical services, 41 (42%); ED, 11 (11%); and hospital, 46 (47%). Seventy-eight (79%) patients demonstrated 111 CT abnormalities: edema, 35 (32%); atrophy, 24 (22%); extra-axial hemorrhage, 14 (13%); old infarct, 12 (11%); new infarct, 11 (10%); intraparenchymal hemorrhage, 6 (5%); skull fracture, 5 (4%); mass, 3 (2%); and foreign body, 1 (1%). Therapeutic and diagnostic alterations in care were made in 38 (39%) patients-35 abnormal and 3 normal CTs. The following alterations occurred: medication administration, 26; withdrawal of life support, 7; additional diagnostic study, 6; neurologic consultation, 6; and intracranial pressure monitoring. 4. No patient survived to discharge. In this subset of resuscitated patients with cardiac arrest, abnormalities on the head CT were not uncommon. Alterations in management did occur in those patients with abnormalities. The indications and impact of head CT in the population of resuscitated patients with cardiac arrest remain unknown, warranting further investigation.


p.Tyr365Cys change in factor VIII: haemophilia A, but not as we know it.
Haemophilia A is caused by a reduction in clotting factor VIII (FVIII). FVIII coagulant activity (FVIII:C) can be measured by three methods; the one-stage activated partial thromboplastin time-based clotting assay, the two-stage Xa generation-based clotting assay and the chromogenic Xa generation-based assay. The FVIII:C of most patients with haemophilia A are concordant regardless of the assay method employed. Up to a third of patients show assay discrepancy, usually with the two-stage and chromogenic assays being much lower than the one-stage assay. Very rarely, patients have been reported with lower one-stage compared to two-stage and chromogenic assays, but here we report that the mutation p.Tyr365Cys accounts for most of these patients and, at least in the UK, is not rare. We have identified this mutation in 23 different families. Affected male index individuals had a lower mean one-stage FVIII:C of 27 iu/dl compared to two-stage FVIII:C mean of 77 iu/dl. Affected individuals had minimal or absent bleeding symptoms and when these were present they were usually in patients with another co-inherited bleeding disorder. Affected individuals often had surgery without the need to correct the one-stage FVIII:C.